PROJECT SUMMARY The hair follicle is a complex mini-organ that undergoes continuous cycles of regression (catagen), quiescence (telogen), growth (anagen), and shedding (exogen) in a process known as the hair cycle. A number of hair loss disorders including androgenetic alopecia, the most common form of hair loss in humans, are thought to be due to defects in hair cycle progression. The therapeutic options for such hair loss disorders nonetheless remain limited, owing to an incomplete understanding of the molecular mechanisms that govern hair cycling. Recent evidence from our lab and others uncovered a role for JAK/STAT signaling in the control of hair cycling. Specifically, we demonstrated that JAK/STAT5 signaling downstream of Oncostatin M produced by Trem2+ dermal macrophages maintains hair follicle quiescence during telogen. Meanwhile, previous studies have shown that JAK/STAT3 signaling may play the opposite role in hair cycling, since STAT3 epidermal knockout mice remain arrested in telogen; however, the mechanism by which JAK/STAT3 governs the hair cycle, including its upstream activating factor(s), remain unknown. In this study, we will investigate the molecular mechanisms of JAK/STAT3-driven control of the hair cycle, with a focus on the telogen-to-anagen transition. In Aim 1, we will define the temporal and spatial pattern of JAK/STAT3 signaling in the hair follicle and the surrounding dermal environment throughout the hair cycle. In Aim 2, we will interrogate the functional role of JAK/STAT3 in hair cycling by both pharmacologically and genetically perturbing JAK/STAT3 signaling at specific points in the hair cycle. To achieve this, we will use a number of small-molecule JAK and STAT3 inhibitors, as well as inducible Cre-driven knockout mice that ablate STAT3 in specific skin and hair follicle compartments. In Aim 3, we will investigate the role of leptin, a 16 kDa hormone peptide that has been extensively studied in the context of obesity and metabolism, as a potential upstream activating factor of JAK/STAT3 signaling in hair cycling. Canonical leptin signaling is known to activate the JAK2/STAT3 axis, and previous studies as well as our Preliminary Data demonstrate that leptin signaling is required for the telogen-to-anagen transition, thereby inviting further investigation of leptin as a candidate upstream factor of JAK/STAT3 in anagen induction. Neither JAK/STAT3 nor leptin have been extensively studied in hair biology relative to other signaling pathways and hormones, therefore, these studies will greatly expand our current understanding of skin and hair follicle homeostasis. Furthermore, we anticipate that our findings can be extrapolated to provide novel insight into the pathogenesis of hair loss disorders, and thereby identify novel therapeutic targets for different types of alopecia.